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Rapid CommunicationMinireview—Special Section on Highlights from IUPHAR

The Odd Sibling: Features of β3-Adrenoceptor Pharmacology

Hana Cernecka, Carsten Sand and Martin C. Michel
Molecular Pharmacology November 2014, 86 (5) 479-484; DOI: https://doi.org/10.1124/mol.114.092817
Hana Cernecka
Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands (H.C.); Department of Pharmacology, University of Duisburg-Essen, Essen, Germany (C.S.); and Department of Pharmacology, Johannes Gutenberg University, Mainz, Germany (M.C.M.)
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Carsten Sand
Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands (H.C.); Department of Pharmacology, University of Duisburg-Essen, Essen, Germany (C.S.); and Department of Pharmacology, Johannes Gutenberg University, Mainz, Germany (M.C.M.)
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Martin C. Michel
Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands (H.C.); Department of Pharmacology, University of Duisburg-Essen, Essen, Germany (C.S.); and Department of Pharmacology, Johannes Gutenberg University, Mainz, Germany (M.C.M.)
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Abstract

β3-Adrenoceptor agonists have recently been introduced for the treatment of overactive urinary bladder syndrome. Their target, the β3-adrenoceptor, was discovered much later than β1- and β2-adrenoceptors and exhibits unique properties which make extrapolation of findings from the other two subtypes difficult and the β3-adrenoceptor a less-understood subtype. This article discusses three aspects of β3-adrenoceptor pharmacology. First, the ligand-recognition profile of β3-adrenoceptors differs considerably from that of the other two subtypes, i.e., many antagonists considered as nonselective actually are β3-sparing, including propranolol or nadolol. Many agonists and antagonists classically considered as being β3-selective actually are not, including BRL 37,344 ((±)-(R*,R*)-[4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]phenoxy] acetic acid sodium hydrate) or SR 59,230 (3-(2-ethylphenoxy)-[(1S)-1,2,3,4-tetrahydronaphth-1-ylamino]-(2S)-2-propanol oxalate). Moreover, the binding pocket apparently differs between the human and rodent β3-adrenoceptor, yielding considerable species differences in potency. Second, the expression pattern of β3-adrenoceptors is more restricted than that of other subtypes, particularly in humans; this makes extrapolation of rodent findings to the human situation difficult, but it may result in a smaller potential for side effects. The role of β3-adrenoceptor gene polymorphisms has insufficiently been explored and may differ even between primate species. Third, β3-adrenoceptors lack the phosphorylation sites involved in agonist-induced desensitization of the other two subtypes. Thus, they exhibit downregulation and/or desensitization in some, but not other, cell types and tissues. When desensitization occurs, it most often is at the level of mRNA or signaling molecule expression. All three of these factors have implications for future studies to better understand the β3-adrenoceptor as a novel pharmacological target.

Footnotes

    • Received March 20, 2014.
    • Accepted May 30, 2014.
  • Work in the author laboratories was supported in part by a grant from Astellas Europe B.V. and through Coordination Theme 1 (Health) of the European Community's FP7 [Grant agreement number HEALTH-F2-2008-223234]. H.C. is employed by a grant from Astellas to her institution. C.S. does not report a conflict of interest. M.C.M. has received consultant honoraria and/or research support in the β3-adrenoceptor field from AltheRX, Astellas, and Boehringer Ingelheim; he currently is an employee of Boehringer Ingelheim.

  • dx.doi.org/10.1124/mol.114.092817.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 86 (5)
Molecular Pharmacology
Vol. 86, Issue 5
1 Nov 2014
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Rapid CommunicationMinireview—Special Section on Highlights from IUPHAR

The Odd Sibling: Features of β3-adrenoceptor Pharmacology

Hana Cernecka, Carsten Sand and Martin C. Michel
Molecular Pharmacology November 1, 2014, 86 (5) 479-484; DOI: https://doi.org/10.1124/mol.114.092817

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Rapid CommunicationMinireview—Special Section on Highlights from IUPHAR

The Odd Sibling: Features of β3-adrenoceptor Pharmacology

Hana Cernecka, Carsten Sand and Martin C. Michel
Molecular Pharmacology November 1, 2014, 86 (5) 479-484; DOI: https://doi.org/10.1124/mol.114.092817
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